Glaucoma surgery

ABSTRACT

Eye diseases such as glaucoma can be treated using a composition containing cross-linked hyaluronic acid or a cross-linked salt of hyaluronic acid such as sodium hyalurate. The composition can be a monophasic gel. The composition can include a cross-linking agent such as 1,4-butanediol diglycidylether. The composition can contains about 2.25% (w/w) of the salt of hyaluronic acid. The composition can have a cross-linking rate of about 0.5 to 50%.

This application claims priority of U.S. Application No. 61/096,654,filed Sep. 12, 2008, the entire contents of which is hereby incorporatedby reference

BACKGROUND OF THE INVENTION

1. Field of the Invention

A gel facilitates perforating and non-perforating glaucoma surgery.

2. Description of the Related Art

Glaucoma is a group of eye diseases that gradually steal sight withoutwarning. In the early stages of the disease, there may be no symptoms.Experts estimate that half of the people affected by glaucoma may notknow they have it.

There is no cure for glaucoma. However, medication or surgery can slowor prevent further vision loss. The appropriate treatment depends uponthe type of glaucoma among other factors.

Primary open angle glaucoma is the most common form of glaucoma. Ithappens when the eye's drainage canals become clogged over time. Theinner eye pressure (also called intraocular pressure or IOP) risesbecause the correct amount of fluid can't drain out of the eye. Withopen angle glaucoma, the entrances to the drainage canals are clear andshould be working correctly. The clogging problem occurs further insidethe drainage canals, similar to a clogged pipe below the drain in asink. Most people have no symptoms and no early warning signs. If openangle glaucoma is not diagnosed and treated, it can cause a gradual lossof vision. This type of glaucoma develops slowly and sometimes withoutnoticeable sight loss for many years. It usually responds well tomedication, especially if caught early and treated.

Angle closure glaucoma is also known as acute glaucoma or narrow angleglaucoma. It is much more rare and is very different from open angleglaucoma in that the eye pressure usually rises very quickly. Thishappens when the drainage canals get blocked or covered over, like asink with something covering the drain. With angle closure glaucoma, theiris is not as wide and open as it should be. The outer edge of the irisbunches up over the drainage canals, when the pupil enlarges too much ortoo quickly. This can happen when entering a dark room.

Treatment of angle closure glaucoma usually involves surgery to remove asmall portion of the outer edge of the iris. This helps unblock thedrainage canals so that the extra fluid can drain. Symptoms of angleclosure glaucoma may include headaches, eye pain, nausea, rainbowsaround lights at night, and very blurred vision.

Secondary glaucoma can occur as the result of an eye injury,inflammation, tumor or in advanced cases of cataract or diabetes. It canalso be caused by certain drugs such as steroids. This form of glaucomamay be mild or severe. The type of treatment will depend on whether itis open angle or angle closure glaucoma.

The success of glaucoma surgery depends on the modification of woundhealing. The aim is to limit a healing process and to avoid fibroustissue formation that are natural biologic responses and areindispensable for all other surgical procedures. Risk factors includeage, race, type of glaucoma, conjunctival inflammation and aphakia.

FIG. 1 shows the process of wound healing in glaucoma filteringprocesses.

As shown in FIG. 1, the stages of wound healing include injury,inflammation, coagulation (clot formation), cellular migration andproliferation, angiogenesis, and scar formation. There are phenomenaassociated with each stage. For example, inflammation includes vascularpermeability, cellular infiltration, plasma proteins, fibrinogen,fibronectin, platelets and cellular procoagulant. Cellular migration andproliferation is associated with fibroblasts, neurophils, macrophages,monocytes and epithelial cells. Scar formation is associated withcollagen formation and cross linking.

The strategies to interfere with the process of wound healing afterglaucoma surgery include meticulous surgical technique to minimizetrauma to the conjunctiva, episclera and iris to decrease leakage ofplasma proteins. Other strategies interfere with the process of woundhealing at the different stages shown in FIG. 1.

Treatment at the inflammation stage include non-steroidalanti-inflammation drugs (NSAIDs), including aspirin, indomethacin,fluiboprofen. Steroidal drugs used at the inflammation stage can includeprednisolon, fluoromethalon and dextramethssone.

Treatment at the coagulation (clot formation) stage can includethrombolytic drugs, urokinase, streptokinase and t-PA. Treatment at thecellular migration stage can include mitomicine C and 5 FU. Treatment atthe scar formation stage includes Beta-aminopropionitrile,D-penicillamine and colchicine.

However, there is a continuing need for treatments that will increasethe likelihood of a successful outcome from eye surgery, especiallyglaucoma surgery.

SUMMARY OF THE INVENTION

It is therefore an object of the invention to overcome one or moredisadvantages associated with the related art.

The invention, in part, pertains to a method of treating glaucoma orother eye disease that includes injecting an eye of a patient withviscoelastic material made of a cross-linked high water content(hydrogel) biocompatible gel of hyaluronic acid (HA) or its salt,preferably sodium hyaluronate in the form of a monophasic gel. Thecross-linking agent can be 4-butanediol diglycidylether. The monophasicgel can contain about 2.25% (w/w) of the salt of hyaluronic acid, andthe cross linking rate can be about 0.5-50%. Injection can be under ascleral flap or under conjunctiva. The method can be perforating or nonperforating surgery such as trabeculectomy, visocanalostomy or deepsclerectomy.

The method can be a trabeculectomy that includes applying peribulbaranesthesia, dissecting a scleral flap, performing an iridotomy to allowan iris to fall back, suturing the scleral flap, injecting thecross-linked sodium hyaluronate under the scleral flap, and injectingthe cross-linked hyaluronic acid or its salt under conjunctiva.

The method can be a visocanalostomy that includes applying peribulbar ortopical anesthesia, dissecting a first scleral flap at a site with atleast one apparent collecting channel, dissecting a second scleral flapclose to a ciliary body, unroofing a Schlemms' canal (SC) by pulling onthe second scleral flap, creating a Trabeculo-Descement-Membrane window,inserting a canula into two ostia of the Schlemms' canal, repeatedlyinjecting into the two ostia the cross-linked hyaluronic acid or itssalt, injecting into at least one scleral flap the cross-linkedhyaluronic acid or its salt, and injecting the cross-linked hyaluronicacid or its salt under conjunctiva to create a large conjunctival bleb.

The method can be a deep sclerectomy that includes applying peribulbaror topical anesthesia, dissecting a first scleral flap into clearcornea, dissecting a second scleral flap close to a ciliary body, whenreaching a Schlemm's canal, unroofing the second scleral flap, creatinga Trabeculo-Descement-Membrane window, excising the second scleral flap,injecting into at least one scleral flap the cross-linked hyaluronicacid or its salt; and injecting the cross-linked salt of hyaluronic acidunder conjunctiva to create a large conjunctival bleb.

The invention, in part, pertains to a composition for application duringeye surgery that can include a cross linked high water content(hydrogel) biocompatible viscoelastic gel, and a pharmacologicallyacceptable carrier.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory and areintended to provide further explanation of the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

The accompanying drawings are included to provide a furtherunderstanding of the invention. The drawings illustrate embodiments ofthe invention and together with the description serve to explain theprinciples of the embodiments of the invention.

FIG. 1 shows the stages of wound healing.

FIG. 2 shows a particular process of manufacturing of monophasiccross-linked gels of HA, monodensified (3 first steps) or polydensified(2 additional steps).

FIG. 3 is a comparison of phases, where FIG. 3 a shows a monophasic geland FIG. 3 b shows a biphasic gel, made of cross-linked particles in anon cross-linked gel carrier.

FIG. 4 shows a schematic of eye injury and therapy where hyaluronic acidof the invention is employed.

FIG. 5 is a photograph of an eye at the end of non perforating surgery,when the surgeon injects cross-linked gel under the sclera flap.

FIG. 6 shows the outflow of the aqueous humor through the filtering blebuntil the subconjunctival space filled with cross-linked gel of theinvention during perforating surgery.

FIG. 7 is a photograph of an eye after glaucoma surgery according to theinvention and showing the proeminence of the subconjunctival bleb thanksto slit lamp exam.

FIG. 8 shows the outflow of the aqueous humor through the filtering blebthrough the sclera cavity and until the subconjunctival space filledwith cross-linked gel of the invention during non-perforating surgery.

DETAILED DESCRIPTION OF THE INVENTION

Advantages of the present invention will become more apparent from thedetailed description given hereinafter. However, it should be understoodthat the detailed description and specific examples, while indicatingpreferred embodiments of the invention, are given by way of illustrationonly, since various changes and modifications within the spirit andscope of the invention will become apparent to those skilled in the artfrom this detailed description.

Glaucoma is a progressive disease characterized by an optic neuropathythat will induce characteristic visual field defects. The main riskfactor for glaucoma is high intraocular pressure (IOP) however otherrisk factors have been recognized.

Today the only evidence based treatment for glaucoma is lowering of theIOP. The first choice is in the majority of cases medical therapy. Ifdespite maximal medical therapy the disease progresses, laser therapy orsurgery is advocated.

Trabeculectomy is the most frequent surgical procedure chosen by thesurgeons. It is a perforating filtering procedure that creates a fistulabetween the anterior chamber and the sub-conjunctival space.Trabeculectomy however has a number of potentially serious side effects:athalamy, hypotony, choroid effusion, endophthalmitis. The success rateof this procedure depends on the permeability of the fistula and thepresence of a filtering conjunctival bleb.

Scarring of the tissues is the most frequent cause of failure, andsubstances have been introduced to influence the rate of fibrosis at thesurgical site. MMC and 5FU, two anti-mitotic drugs, are used byapplication on the sclera and under the conjunctiva to inhibitfibroblasts and vascular endothelium proliferation. Unfortunately, thesesubstances may lead to severe complications with sight-threateningconsequences.

In order to avoid operatives and post-operatives complications seen withtrabeculectomy, other, non-perforating procedures have been introduced.Implants used until now have been made of collagen or cross-linked HA(product SKGEL from Corneal). Those products are solid implant that donot adapt to the cavity shapes, and cannot be injected under theconjunctiva (because they are not gels but solids). In Deep Sclerectomy(DS) with or without solid implant and Viscocanalostomy (VCS) a largedescemetic window is created and the Schlemm's canal (SC) is cleanedwith abrasion of the juxta-canalicular tissue. This allows the aqueoushumor to percolate through the very thin descemetic membrane andSchlemm's canal, to collect in the deep scleral bed and to be evacuatedeither via the collector channels and aqueous veins or through theconjunctival filtering bleb. Viscoelastic substances are actually usedto maintain the intrascleral cavity open as well as a patentconjunctival bleb. In VCS, a viscoelastic is injected into the Schlemm'scanal in order to enlarge and eventually micro-perforate the later.

In one approach, the viscoelastic can be a non cross-linked hyaluronicacid. However, this substance has only a short life-time and cannotinduce long-term space-maintenance.

The major reason for failure of these procedures is fibrosis either atthe level of the scleral cavity or at the level of the conjunctiva.

The use of a substance that will remain for a prolonged time asspace-maintainer under the scleral flap and/or the conjunctival bleb mayimprove the surgical success rate of penetrating and non penetratingglaucoma surgery.

A cross-linked biocompatible viscoelastic gel is thus indicated forperforating and non perforating glaucoma surgery. Injected under thescleral flap and/or the conjunctiva, it acts for a prolonged time as aspace filler and a drainage device and limits the postoperative fibrosisthus improving the surgical success rate. Its gel texture, capable toadapt to any cavity shape and to fill the whole space, creates abiocompatible neighborhood that avoids cell proliferation anddifferentiation into fibrous tissue. In a preferred embodiment, itsslowly resorbable property increases its tolerance andnon-immunogenicity and leads to the non fibrous healing of the sclera orconjunctival tissue. This preserves the regeneration of specialized andfunctional cells and maintains an efficient uveo-scleral outflow ofaqueous humour through tissues.

There are three fundamental characteristics of the gel injected that areneeded in order to obtain a more successful surgical outcome:

1. The product has to drain water and not clog the surgically createdcanals, and thus can be made of a high water content so that it couldconduct the aqueous humor flow

2. The product can be a biocompatible viscoelastic gel, in order tolimit scarring formation which would induce closure of the drainage

3. The product is cross-linked in order to be stable and to maintain theabove mentioned features.

In more detail, a high water content is obtained from using a hydrogelmaterial and the injected product is prepared using an aqueouspharmacologically acceptable medium.

To obtain a biocompatible viscoelastic gel, the following is preferred:

-   -   The biocompatible viscoelastic gel is preferably made of natural        polysaccharide(s) such as hyaluronic acid or its salt,        chondroitin sulfate, keratan, keratan sulfate, heparin, heparin        sulfate, alginate, cellulosic derivatives, chitosan, xanthan, or        one of the salts thereof. Such biocompatibility avoids        inflammation, foreign body reaction, or any biological signal        which would increase scarring process.    -   The gel texture, capable to adapt to any cavity shape and to        fill the whole space, creates a biocompatible neighborhood        environment that would avoid cells proliferation and        differentiation into fibrous scarring tissue.    -   In a preferred embodiment, the gel injected contains hyaluronic        acid (HA), or one of the salts thereof. HA has biological        properties that enhance this biocompatible characteristic and        limits scarring formation.    -   A minimum content of polysaccharide is about 0.1% and a maximum        is about 20%. For a concentration below about 0.1%, the        viscoelastic behavior of HA is lost, and this means that no        flexible network is obtained and thus efficacy of the        cross-linking is uncertain. The biocompatibility of HA        derivatives showed signs of intolerance when concentration was        over about 20%.    -   Pharmacologically active ingredients can be added into the gel        in order to further limit scarring process (antimitotic agent,        anti inflammatory agent, etc).

Regarding the creation of a cross-linked network, the following shouldbe noted:

-   -   The cross-linking agent is a bifunctional or a polyfunctional        molecule, which can be at least one of epoxys (for example 1,4        butanediol diglycidylether (BDDE) or 1,2,7,8-Diepoxyoctane        (DEO)), divinylsulfone (DVS) or carbodiimide (for example        1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) or        N-cyclohexyl-N-(4-methylmorpholinium) ethyl carbodiimide (CMC)).        A preferred embodiment corresponds to the injection of a gel        cross-linked with BDDE, which is reported as the less toxic        agent among the above listed ones.    -   Cross-linking ratio w/w can be chosen between about 0.5% to        about 50%. A preferred embodiment is between about 2% to about        20%. The cross-linking provides long term stability to the        polysaccharide in order to maintain drainage functions. Any        addition of cross-linking within the polysaccharide gel        increases its stability, even at low level such as about 0.5%.        Significant stabilization of several months in intradermal        tissue has been described in literature with level of        cross-linking between about 2 to about 20%. Beyond a certain        level of cross-linking, the gel becomes a solid and is no longer        injectable neither adaptable to a cavity shape. The maximum        level of cross-linking also depends on the cross-linker agent.    -   A preferred embodiment is a monophasic gel, corresponding to an        homogeneous viscoelastic cross-linked gel network    -   Another preferred embodiment is a polydensified monophasic gel,        such as is mentioned in U.S. Publication 2007/0196426        Biocompatible cross-linked gel.    -   Solid particles or fragments highly cross-linked can be inserted        in the injected gel according to above description, in order to        obtain a biphasic composition, with a biocompatible cross-linked        viscoelastic polysaccharide(s) gel as the carrier.    -   Molecules such as polyol or antioxidant can be added to the        cross-linked gel in order to enhance its stability

An effective viscoelastic gel is formed from a salt of hyaluronic acid.Preferably the salt is a sodium salt, i.e., sodium hyaluronate. However,other counterions can be used, such as potassium, lithium, magnesium,ammonium, etch. Also, mixed salts can be used.

The salt of hyaluronic acid yields a superior viscoelastic as amonophasic, which can be attained by cross-linking. A typical crosslinking agent is 4-butanediol diglycidylether. The 4-butanedioldiglycidylether can be modified with glycidyl isopropyl ether.

In a preferred embodiment, the viscoelastic material is an injectableand resorbable cross-linked gel of hyaluronic acid from biofermentationorigin. The gel can be presented in a 1 mL prefilled glass syringe, andsterilized by moist heat by autoclave. The viscoelastic can be amonophasic gel.

In a preferred embodiment, the viscoelastic material is a sterile,pyrogen free, colorless, transparent, viscoelastic and cohesive gel,made of cross-linked sodium hyaluronate (NaHA). The cross-linking agent,BDDE (1,4-butanediol diglycidylether), creates covalent bonds betweenNaHA chains (ether bonds). The NaHA concentration equals about 2.25%(w:w) and cross-linking rate, corresponding to the ratio [mass ofBDDE+(mass BDDE+mass NaHA)]×equals about 5%.

The NaHA concentration is not restricted to about 2.25%, but can rangefrom about 1.5% to about 3%. The cross-linking rate is not restricted toabout 9%, but can range from about 5% to about 20%.

The hyaluronic acid of the present invention can be a natural polymer(glycosaminoglycan) composed of alternating residues of themonosaccharides D-glucuronate and N-acetyl-D-glucosamine, linked inrepeating units. This polysaccharide is a constituent of all connectivetissues in humans and all vertebrates. It is chemically, physically, andbiologically identical in all species and has extraordinarily goodbiological compatibility. The cross-linking agent is also the same:1,4-butanediol diglycidylether (BDDE), the safest of the cross-linkingagents commonly used.

The method of manufacturing of a cross-linked monophasic gel ofhyaluronic acid is typically shown in FIG. 2. The amorphous structure 10of pure hyaluronic acid (HA) or its salt has little organization. HA canbe spatially organized 20 in a basic solution and then reticulated to afirst level 30, thanks to the addition of a cross-linker underappropriate conditions. This step could be followed by terminalpurification in order to obtain a monophasic monodensified cross-linkedgel of hyaluronic acid, or followed by additional steps in order toobtain a monophasic polydensified cross-linked gel of hyaluronic acid,according to patent application US2007/0196426. Preferably the firstlevel of reticulated HA can be elongated 40. A second reticulation 50can follow, with the adjunction of supplementary HA followed by terminalpurification.

The result is a monophasic material that is shown in FIG. 3, where FIG.3 a shows the preferred cohesive monophasic gel compared to thedispersive biphasic material shown in FIG. 3 b, made of cross-linkedparticles of HA embedded into a non cross linked gel of HA. Since thisnon cross-linked substance has only a short life-time and cannot inducelong-term space-maintenance and since solid particles cannot fill thewhole cavities, this biphasic composition cannot improve the surgicalsuccess rate of penetrating and non penetrating glaucoma surgery. Solidparticles or highly cross linked fragments can be embedded into a gel ofthe invention in order to obtain a biphasic composition, with abiocompatible cross linked viscoelastic gel as the carrier.

FIG. 4 shows a schematic of eye injury and therapy where the hyaluronicacid of the invention is employed. As opposed to the conventionaltherapy shown in FIG. 1, the utilization of the viscoelastic materialmade of hyaluronic acid (or one of the salts thereof) of the inventionprovides at least the following advantages:

-   -   Inhibition of cytokine production,    -   Inhibition of cell migration and phagocytosis, and    -   Inhibition of lymphocyte transformation.

These advantages come in addition to the biocompatible neighborhood thatavoids cell proliferation and differentiation into fibrous tissue.

In practice, the viscoelastic cross-linked gel of the invention is abiocompatible hydrogel which works by being injected during the glaucomasurgery in the scleral flap, or between the sclera and the conjunctivaein order to provide a space-occupying viscoelastic supplement and tocontrol the wound healing process. It results in a bleb keeper.

One typical application of the viscoelastic material of the invention isin a trabeculectomy. A trabeculectomy can have the following surgicalprocedure:

Surgical Procedure:

Anesthesia is peribulbar (Lidocaine-Adrenalin) The conjunctival flap isfomix-based. After diathermy of the scleral bed, a 4 mm×4 mm rectangularscleral flap of approximately one-half scleral depth is dissected to thelimbus. If necessary a paracenthesis may be done at this stage of thesurgery.

While elevating the scleral flap, a sclerectomy is done by a radialincision made immediately under the flap junction. The iris may prolapsethrough the wound.

A small iridotomy is performed and will allow the iris to fall back.

The scleral flap is sutured with interrupted or releasable 10.0 nylonsutures. At this stage of the procedure viscoelastic material of theinvention is injected under the scleral flap. Conjunctiva is closed withinterrupted or continuous 10.0 nylon sutures.

The viscoelastic material of the invention is injected under theconjunctiva in order to create a large conjunctival bleb. If necessary,BSS is injected into the anterior chamber.

Topical antibiotic and anti-inflammatory drops are prescribedpostoperatively for 1 month.

Another typical application of the material of the present invention isin viscocanalostomy. A procedure for viscocanalostomy can be as follows:

Surgical Procedure:

Anesthesia is peribulbar (Lidocaine-Adrenalin) or topical (tetracaindrops with subconjunctival Lidocaine-Adrenalin). The conjunctival flapis fornix-based.

To avoid damage to Schlemm's canal (SC), the collector channels and theepiscleral vascular bed, diathermy is not used. Instead, hemostasis isachieved by Glypressine embedded (Ferring AG Sweden) sponge applicationon the surgical wound.

A site with at least one apparent collecting channel is chosen and a 5×5mm limbal based rectangular or parabolic, thin superficial scleral flapis dissected 1.5 mm into clear cornea. A second, deep scleral flap isdissected close to the ciliary body.

When reaching SC, the latter is unroofed by gently pulling on thescleral flap and concomitantly peeling the fibrotic lining from thebottom of the canal, procedure continued into a cleavage plane, betweenthe corneal stroma and the Descemet's membrane, creating aTrabeculo-Descemet-Membrane (TDM) window. The bottom of the canal ispeeled and the juxta-canalicular tissue abraised.

As soon as the TDM window is created, percolation of the aqueous humorthrough the remaining peripheral Descemet's membrane and/or SC isobserved. A 150 microns canula is inserted into the two ostia of the SCand the viscoelestic material of the invention is repeatedly injectedinside. The deep flap is excised with micro-scissors and viscoelesticmaterial of the invention is injected in the scleral cavity. Thesuperficial flap is sutured with 2 separate 10-0 nylon sutures.

At this stage of the procedure viscoelestic material of the invention isinjected under the scleral flap. The conjunctiva is sutured using 2separate 10-0 nylon sutures The viscoelestic material of the inventionis injected under the conjunctive in order to create a largeconjunctival bleb. Topical antibiotic and anti-inflammatory drops areprescribed postoperatively for 1 month.

Another typical application of the viscoelastic material of theinvention is in deep sclerectomy. A procedure for a deep sclerectomy isas follows:

Surgical Procedure:

Anesthesia is peribulbar (Lidocaine-Adrenalin) or topical (tetracaindrops with subconjunctival Lidocaine-Adrenalin). The conjunctival flapis fornix-based.

After diathermy of the vascular bed a 5×5 mm limbal-based rectangular,thin superficial scleral flap is dissected 1.5 mm into clear cornea bymeans of a diamond knife. A second, deep scleral flap is dissected closeto the ciliary body.

When reaching SC, the latter is unroofed by gently pulling on the scflap and concomitantly peeling the fibrotic lining from the bottom ofthe canal, procedure continuing into a cleavage plane, between thecorneal stroma and the Descemets membrane, creating aTrabeculo-Descemet-Membrane (TDM) window. The bottom of the canal ispealed and the juxta-canalicular tissue abraised. The second flap isexcised. As soon as the TDM window is created, percolation of theaqueous humor through the remaining peripheral Descemet's membraneand/or SC is observed. The viscoelestic material of the invention isinjected into the scleral cavity.

The first scleral flap is sutured with 2 10.0 nylon sutures. At thisstage of surgery the viscoelestic material of the invention is injectedunder the scleral flap. The conjunctiva is sutured with 2-3 nylonsutures and the viscoelastic material of the invention is injected underthe conjunctiva in order to create a large conjunctival bleb. Topicalantibiotic and anti-inflammatory drops are prescribed postoperativelyfor 1 month.

The trabeculectomy discussed above is an example of perforating surgery.A small incision is made in the conjunctiva, which is then carefullylifted and separated from the sclera, and a half-thickness flap is thendissected up to the edge of the cornea. Then, as is shown in FIG. 6, theviscoelastic material of the invention 60 is injected under the scleraflap 70 as a space maintainer. After the conjunctiva are sutured, theviscoelastic is injected in order to create a large sub-conjunctivalbleb 80.

Non-perforating surgery is typified by viscoanalostomy or sclerectomy.As is shown in FIG. 8, injection of the viscoelastic material of theinvention 60 is injected into the scleral cavity 90 and under theconjunctiva during non-penetrating surgery in order to create thesub-conjunctival bleb 80.

EXPERIMENTAL

A cross-linked hyaluronic acid (XLHA) was utilized as a space-fillingproduct injected intrasclerally and subconjunctivally during glaucomasurgery.

Patients and Methods:

In a non-randomized pilot study the results of XLHA application during19 deep sclerectomies (18 patients), 40 viscocanalostomies (33 patients)and 50 trabeculectomies (50 patients), were retrospectively evaluated.

For the deep sclerectomy series the types of glaucoma were primary openangle (POAG)(42%), primary angle closure (PACG) (21%), exfoliative(11%), congenital (16%), traumatic (5%) and ocular hypertension (5%).Most were combined phaco-deep sclerectomies (37%), followed byredo-glaucoma interventions (26%), simple deep sclerectomies (21%) andcombined deep sclerectomy-trabeculectomy (16%).

For the viscocanalostomy series the types of glaucoma were exfoliative(43%), POAG (38%), dysgenetique (14%) and PACG (5%). Most were simpleviscocanalostomies (76%), followed by combined phaco-viscocanalostomies(15%), combined viscocanalostomy-trabeculectomy (3%),viscocanalostomy-iridectomy (3%) and trabeculectomy (3%). Fortrabeculectomy series the types of glaucoma were exfoliative (50%), POAG(46%), ICE-syndrome (2%) and Axenfeld-Rieger (2%). Most were simpletrabeculectomies (94%) and in 6% combined phaco-trabeculectomy.

Results:

For the deep sclerectomy series the mean pre-operative eye pressure(IOP) was 19.4 mmHg (+−5.2, 12-34) under medical treatment (2.3anti-glaucoma medication per patient, +−1.4, 0-5). The meanpost-operative IOP at the last follow-up was 11.3 mmHg (+−3.6, 6-18)with a mean follow-up of 15.6 weeks (+−10.1, 4-31). One patient was on apressure reducing medication postoperatively. A diffuse filtration blebwas present in all but one case. Of the 9 eyes that underwent UBM showeda prominent subconjunctival bleb and 5 had an easily visibleintrascleral canal.

For the viscocanalostomy series the mean pre-operative IOP was 22.4 mmHg(+−5.7, 14-33) under medical treatment (2.9 anti-glaucoma medication perpatient, +−0.7, 1-4). The mean post-operative IOP at the last follow-upwas 11.3 mmHg (+−3.3, 4-24) with a mean follow-up of 21.2 weeks (+−19.4,0.3-90.6). No patient was on a pressure reducing medicationpostoperatively. A diffuse filtration bleb was present in 87%.

For the trabeculectomy series the mean pre-operative IOP was 22.6 mmHg(+−6.5, 12-40) under medical treatment (2.7 anti-glaucoma medication perpatient, +−0.9, 1-4). The mean post-operative eye pressure at the lastfollow-up was 11.9 mmHg (+−5.1, 2-22) with a mean follow-up of 10.4weeks (+−5.6, 4-28). One patient was on a pressure reducing medicationpostoperatively.

Discussion:

XLHA is easy to handle and easy to adapt to all surgical procedures. Nocomplication related to the use of XLHA was noticed. Blebs remain calmin most cases, associated with few complications. Postoperative pressurereducing medication was suppressed in all patients but 2.

XLHA seems to be a promising aid in the management of the fibrosisprocess following deep sclerectomy, viscocanalostomy and trabeculectomysurgery with good IOP control and diffuse blebs with suggested presenceof XLHA inside blebs on UBM during the follow up period.

Additional aspects of the present invention can be observed in FIG. 5,which shows an eye at the end of non perforating surgery, when thesurgeon injects cross-linked gel under the sclera flap. FIG. 7 shows aneye after glaucoma surgery according to the invention and showing theproeminence of the subconjunctival bleb thanks to slit lamp exam.

In summary, sodium hyaluronate is natural polymer (glycosaminoglycan)obtainable by biofermentation, and is a constituent of all connectivetissues of humans and vertebrates. The material is chemically,physically and biologically identical in all species, and hasextraordinarily good biological compatibility. Cross-linked monophasicgels of this material have been found to be a superior viscoelasticspacer material for eye surgery, especially eye surgery associated withglaucoma.

It is to be understood that the foregoing descriptions and specificembodiments shown herein are merely illustrative of the best mode of theinvention and the principles thereof, and that modifications andadditions may be easily made by those skilled in the art withoutdeparting for the spirit and scope of the invention, which is thereforeunderstood to be limited only by the scope of the appended claims.

What is claimed is:
 1. A method of treating glaucoma or other eyedisease, comprising: during eye surgery, injecting the eye of thepatient with a cohesive monophasic gel comprising a cross-linkedhyaluronic acid or its salt, under a scleral flap and/or conjunctiva ofthe eye, thereby creating and maintaining a conjunctival bleb, whereinthe concentration of the hyaluronic acid in the gel is in a range of0.1% to 20% by weight.
 2. The method according to claim 1, wherein thecross-linked salt of hyaluronic acid is sodium hyaluronate.
 3. Themethod according to claim 1, wherein the cohesive monophasic gelcomprises a cross-linking agent selected from the group consisting of1,4-butanediol diglycidylether, 1,2,7,8-Diepoxyoctane, divinylsulfone,carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide andN-cyclohexyl-N-(4-methylmorpholinium) ethyl carbodiimide.
 4. The methodaccording to claim 1, wherein the cohesive monophasic gel comprisesabout 2.25% (w/w) of the hyaluronic acid or its salt.
 5. The methodaccording to claim 1, wherein the cross-linked hyaluronic acid or itssalt has a cross linking ratio of about 0.5% to about 50%.
 6. The methodaccording to claim 1, wherein the gel is injected under a scleral flapof the patient.
 7. The method according to claim 1, wherein the gel isinjected under conjunctiva of the patient.
 8. The method according toclaim 1, wherein the eye surgery comprises performing a trabeculectomyon the patient.
 9. The method according to claim 8, wherein thetrabeculectomy comprises: applying peribulbar anesthesia; dissecting ascleral flap; performing an iridotomy to allow an iris to fall back;suturing the scleral flap; injecting the gel under the scleral flap; andinjecting the gel under the conjunctiva.
 10. The method according toclaim 1, wherein the eye surgery comprises performing a visocanalostomyon the patient.
 11. The method according to claim 10, wherein thevisocanalostomy comprises: applying peribulbar or topical anesthesia;dissecting a first scleral flap at a site with at least one apparentcollecting channel; dissecting a second scleral flap close to a ciliarybody; unroofing a Schlemms' canal by pulling on the second scleral flap;creating a Trabeculo-Descement-Membrane window; inserting a canula intotwo ostia of the Schlemms' canal; repeatedly injecting the gel into thetwo ostia; injecting the gel into at least one scleral flap; andinjecting the gel under the conjunctiva.
 12. The method according toclaim 1, wherein the eye surgery comprises performing a deep sclerectomyon the patient.
 13. The method according to claim 12, wherein the deepsclerectomy comprises: applying peribulbar or topical anesthesia;dissecting a first scleral flap into clear cornea; dissecting a secondscleral flap close to a ciliary body; when reaching a Schlemm's canal,unroofing the second scleral flap; creating aTrabeculo-Descement-Membrane window; excising the second scleral flap;injecting the gel into at least one scleral flap; and injecting the gelunder the conjunctiva.
 14. The method according to claim 1, wherein theeye surgery is glaucoma surgery.
 15. A method of treating glaucoma orother eye disease, comprising: during eye surgery, injecting the eye ofthe patient with a cohesive monophasic hydrogel comprising across-linked hyaluronic acid or its salt, under a scleral flap and/orconjunctiva of the eye, thereby creating and maintaining a conjunctivalbleb, wherein the concentration of the hyaluronic acid or its salt inthe hydrogel is in a range of 1.5% to 3% by weight, the cross-linkedhyaluronic acid or its salt has a cross linking ratio of 2% to 20%. 16.The method according to claim 15, wherein the concentration of thehyaluronic acid or its salt in the hydrogel is about 2.25% and the crosslinking ratio is about 5%.